Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort.

BACKGROUND & AIMS: Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS: We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS: We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS: In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Achieving competence in colonoscopy: Milestones and the need for a new endoscopic curriculum in gastroenterology training.

Colonoscopy is considered to be the most effective tool for reducing colorectal cancer (CRC) morbidity and mortality. As a result, certifying trainee competence in the performance of colonoscopy is critical to maximizing CRC screening and prevention efforts. Guidelines on training and accreditation around the world have been revised to emphasize the attainment of milestones in the technical and cognitive skills necessary to perform the procedure. To meet this challenge, new evaluation systems have been developed to measure trainee competence through all aspects of colonoscopy training. These changes stem from increased recognition that procedural numbers alone do not necessarily guarantee trainees' proficiency in the performance of colonoscopy. Variability in endoscopic practice and in CRC screening outcomes also point to deficiencies in the current approach towards colonoscopy instruction. However, technological innovations hold great promise in training endoscopists to perform high quality colonoscopy. Furthermore, potential advances in the use of feedback as a training tool provide new avenues for research. This review summarizes the latest evidence on the effort to define, evaluate and promote the achievement of competence in colonoscopy among trainees.